Ep. 92: “Cell Death and Immunity” Featuring Dr. Pascal Meier
Nov 5, 2024
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Dr. Pascal Meier, a Professor at the Institute of Cancer Research in London, dives into the intricate connections between cell death and immunity. He discusses the significance of different cell death types, such as necroptosis and pyroptosis, in shaping immune responses, especially in cancer. The conversation also highlights the revolutionary role of engineered bacteria in enhancing anti-tumor immunity and the implications of chronic inflammation in health. Lastly, Meier shares insights on pursuing personal passions in a scientific career, blending professional and personal growth.
Cell death mechanisms like necroptosis and pyroptosis play crucial roles in activating immune responses against tumors and pathogens.
Regulatory T cells (Tregs) significantly influence tumor immunity by suppressing CD4 T cell differentiation, which is vital for anti-tumor responses.
Engineered bacteria delivering therapeutic agents like interferon gamma to tumors represent innovative strategies to enhance local immune responses in cancer treatment.
Deep dives
The Diverse Role of Cell Death in Immunology
Cell death is a complex process that plays a fundamental role in immunology and tissue homeostasis. Various forms of cell death, including apoptosis, necroptosis, and pyroptosis, have evolved to communicate with the immune system, signaling both danger and the need for a response. While apoptosis is typically considered non-immunogenic, forms of death that result in cellular lysis release alarmins and inflammatory signals that activate immune responses. For example, necroptosis and pyroptosis are particularly effective at alerting the immune system due to the simultaneous release of damage-associated molecular patterns (DAMPs), promoting a heightened immune reaction against pathogens or tumors.
Mechanisms of T Cell Differentiation and Tumor Immunity
Recent research highlights the role of regulatory T cells (Tregs) in shaping tumor immunity, particularly through their interaction with CD4 T cells. The presence of Tregs can inhibit the expansion and differentiation of CD4 T cells into Th1 cells, which are crucial for anti-tumor immunity. Depleting Tregs or enhancing T-bet expression in the tumor environment leads to the activation of CD8 T cells and improved tumor control. Studies show that patients with higher levels of T-bet expressing CD4 T cells have better outcomes, suggesting that manipulating Treg activity could be a promising therapeutic strategy in cancer treatment.
Harnessing Regulatory T Cells for Therapeutic Use
The innovative use of chimeric antigen receptor (CAR) technology targets regulatory T cells to prevent unwanted immune responses, such as graft-versus-host disease (GVHD). By directing CAR Tregs against activated antigen-presenting cells, researchers aim to generate localized immune suppression, effectively reducing the risk of adverse reactions following bone marrow transplants. These engineered Tregs exhibit enhanced suppressive capabilities, demonstrating significant potential in managing graft acceptance without compromising the immune response to leukemia. This approach reflects a shift towards utilizing the body's regulatory mechanisms for therapeutic benefits in complex immunological scenarios.
Targeting Inflammation and Fibrosis in Heart Failure
A deeper understanding of macrophage behavior in heart failure reveals that Cx3CR1 macrophages orchestrate inflammatory responses that lead to fibrosis. The presence of the transcriptional co-activator BRD4 in these macrophages promotes the expression of IL-1 beta, activating profibrotic responses that exacerbate heart failure outcomes. By intervening in this signaling cascade, researchers have shown that knocking out BRD4 or directly inhibiting IL-1 beta can prevent heart failure progression. These findings point to the potential of targeted therapies aimed at modulating macrophage activity and reducing inflammation, paving the way for novel treatments in cardiac health.
Synthetic Biology for Tumor Treatment
The use of engineered bacteria to deliver therapeutic agents like interferon gamma directly to tumors represents a cutting-edge approach in cancer treatment. The described method employs a non-toxic E. coli strain programmed to release interferon gamma in response to its own population density, enhancing local immune responses without systemic toxicity. This targeted therapy not only activates T cells but also improves the tumor microenvironment, fostering an immune-mediated attack against cancer cells. By combining this bacterial therapy with immune checkpoint inhibitors, the synergistic effects could potentially improve patient outcomes significantly in the fight against cancer.
Dr. Pascal Meier is a Professor and Group Leader at the Institute of Cancer Research in London, England. His group investigates the complex relationship between cell death, immunity, and tumorigenesis. Particularly, they are focused on the role of cell death and inflammation in adaptation to tissue stress, treatment resistance, and tumour surveillance.
New Potential for Cancer Immunotherapy – Researchers have identified a new type of immune cell called stem-like CD4 T cells that play an important role in anti-tumor immunity.
An Improved Treg Therapy – Human OX40 ligand-specific CAR-Tregs may be a potent cellular therapy to control allo- and autoimmune diseases.
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